Recently, as the standard of living is elevated, the average span of human beings' lives is lengthened and the importance of the aged people is increased. Upon examining the cause of death of Korean people, brain diseases such as stroke, dementia, mental disorders and behavior disorders occupy the high rank of death cause, following cancers and diseases of the circulatory system, and rank the top among single organ diseases (Korean Statistics Yearbook, death toll according to sex, age and death cause, 1996). Representative brain diseases include Alzheimer's disease (AD) (Furuta, A. et al., Am. J. Pathol., 1995, 146, 357-367; Good, D. F. et al., Am. J. Pathol., 1996, 149(1), 21-28), multiple sclerosis (MS) (Takeda, A. et al., Neuroscience letters, 1996, 21, 17-20), Lou Gehrig's disease (amyotrophic lateral sclerosis: ALS) (Rosen. D. R. et al., Nature, 1993, 362, 59-62), Parkinson's disease (PD) (Bowling, A. C. and Beal, M. F., Life Sci., 1995, 56(14), 1151-1171), stroke, ischemia and the like. Particularly, in case of senile brain diseases including Alzheimer's disease, Parkinson's disease and stroke, oxidative stress accompanying the formation of a radical in a cerebral cell is one of the important etiological factors (Smith, M. A., J. Neurochem., 1997, Supp. Sl, 69, 19).
The oxidative stress means damage of cells or tissues by toxic free radicals and it is known that neuronal damage by the oxidative stress is involved in damage of brain cells which occurs during normal aging and neurodegenerative disease such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, dementia and the like (Good, D. F. et al., Am. J. Pathol., 1996, 149(1), 21-28; Bowling, A. C. and Beal, M. F., Life Sci., 1995, 56(14), 1151-1171; Smith, M. A., J. Neurochem., 69, 1997, Supp. Sl, 19). In the brain tissues, a large quantity of oxygen is consumed to produce ATP by oxidizing sugar. Generally, an adult consumes 3.5 ml of oxygen per minute for 100 g of brain tissue. Though the brain weight is only 2% of the body weight, the oxygen consumption is 20% of the total and thus, the partial pressure of oxygen in the brain is great. As the partial pressure of oxygen in the brain is increased, activity of glutamate decarboxylase is reduced or the oxygen free radical formation is increased, inducing convulsion (Halliwell, B., and Gutteridge, J. M. C., Free Radicals in Biology and Medicine, 1989, 2nd Ed, Clarendon Press, Oxford). Particularly, the brain tissue is known to be susceptible of free radical attack since the cerebral cells do not have sufficient defense mechanisms and contains a high concentration of long chain unsaturated fatty acids which are liable to be oxidized and metal ions (Fe2+, Cu2+) which are used as a catalyst upon radical formation.
In the nervous system of mammals, over-excitation of the excitatory amino acids system (EAAs system) induces diseases such as epilepsy, Alzheimer's disease, Parkinson's disease, stroke, metal diseases (trauma) and the like, in which oxidative stress caused by increase of free radicals takes part in the induction of such diseases (Rosen. D. R. et al., Nature, 1993, 362, 59-62; Pellegrini-Giampietro, D. E. et al., J. Neurosci, 1990, 10, 1035-1041). Substances activating the excitatory amino acids system to cause brain damage is called as excitotoxins and the excitatory amino acids system overexcited by the excitotoxins induces introduction of ions into nerve cells and free radical production, causing damage of the nerve cells. Glutamate receptor in the excitatory amino acids system is a kind of a ligand-gated ion channel and is classified into NMDA (N-methyl-D-aspartate), AMPA (α-amino-4-isoxazole-propionic acid), kainic acid (KA) receptor according to antagonist selectivity. Over-stimulation of these receptors causes damage of nerve cells. When NMDA receptor is over-stimulated, lipid, protein and nucleic acid which are components of a cell are decomposed due to the introduction of Ca2+ while when non-NMDA receptors are over-stimulated, Na+ is introduced, causing swelling of nerve cells. Also, when kainic acid, a non-NMDA receptor, is activated, damage of nerve cells is induced by the production of a large quantity of reactive oxygen species (hereinafter referred to as “ROS”) (Olney, J. W. et al., Brain Res, 1974, 77, 507-512). The kainic acid which is a strong excitotoxin in the central nerve system shows acute or subacute epileptiform activity lasting for several hours or several days and ultimately causes irreversible neuropathological change in glia, myelin sheaths and the like as well as nerve-cells (Sperk, G., Prog. Neurobiol, 1994, 42, 1-32). In addition, the kainic acid directly induces brain damage and releases glutamate in an amount to show cerebral toxicity (Roberts, J. C. and Francetic, D. J., Anal. Biochem, 1993, 211, 183-187). The kainic acid-induced neuronal death results from destruction of cell membrane caused by production of ROS and such neurotoxicity is prevented by administration of an antioxidant (Coyle, J. T., and Puttfarcken, P. Science, 1993, 262, 689-695).
In recent, researches for substances selectively inducing oxidative stress in the brain have been actively conducted and also researches for protective agent against oxidative stress are actively conducted. Protective agents against ROS existing in cells include glutathione (Roberts, J. C. and Francetic, D. J. Anal. Biochem, 1993, 211, 183-187; Raymond C. et al., J. Nutr., 1995, 125, 3062-3070; Marcos M. et al., J. Mechanisms of ageing and development, 1995, 84, 77-81), α-tocopherol (Hoekstra, W. G., Fed. Proc., 1975, 34, 2083-2089; Kormbrist, D. J. and Movis, R. D., Lipids, 1980, 15, 315-322; Tappel, A. L., Ann. N.Y. Acad. Sci., 1980, 355, 18-31; Reddy C. C. et al., Life Sci., 1982, 31, 571-576), vitamin A (Ernster, L. and Nordenbrand, K., Methods in Enzymology, 1967, 10, 574-580), vitamin C (Rustia, M., J. Natl. Cancer Inst., 1975, 55, 1389-1393), selenium (Hoekstra, W. G. Fed. Proc., 1975, 34, 2083-2089) and the like, and antioxidant enzymes include SOD (McCord and Fridovich, J. Biol. Chem., 1969, 224, 6049-6055), catalase, glutathione peroxidase (Roberts, J. C. and Francetic, D. J., Anal. Biochem., 1993, 211, 183-187; Tappel, A. L. Methods in Enzymology, 1978, 52, 506-523), glutathione S-transferase (Roberts, J. C. and Francetic, D. J., Anal. Biochem., 1993, 211, 183-187; Burk, R. F. et al., Biochem. Biophys. Acta., 1980, 618, 35-41), glutathione reductase (Tietze, F., Anal. Biochem., 1969, 27, 502-522; Floreani M, et al., FASEB J., 1997, 11, 1309-1315; Phillis, J. W., Prog. Neurobiol., 1994, 42, 441-448), quinone reductase (Prestera, T. et al., Proc. Natl. Acad. Sci. USA, 1993, 90, 2969) and the like.
Up to date, there have been reported effects of various natural antioxidants for antioxidant protection against oxygen radical produced in cells, which are mainly related to antioxidant functions of herbs or food ingredients in liver tissue, while giving a poor showing in connection with antioxidation in brain tissue (Park, J. C. et al., J. Korean Soc. Food Nutr., 1996, 25, 588-592; Kim, M. R. et al., J. Food. Sci. Nutr., 1997, 2, 207; Kim, Mee Ree, et al., Food Res. Intl., 1999, 31(5), 389-394). Meanwhile, researches for development of a treating agent to prevent senile brain diseases are focused on neuroprotective treatment. In recent, scavengers of free radicals, calcium antagonists, NMDA and non-NMDA receptor antagonists and the like have been developmed and partially used. However they are not yet proved to be stable in the human body as an antioxidant for brain protection (Olney, J. W. et al., Science, 1991, 254, 1515-1518; Brouillet, E. and Beal M. F., NeuroReport., 1993, 4, 387-390; Kim, W. J. Kwon, J. S., Arch. Pharm. Res., 1999, 22, 35-43). From this point of view, edible plant resources which we commonly eat are verified for their stability in the human body to some degree. However, researches are mainly focused on their antioxidant effects in the liver tissue and research aiming at brain protection is insufficient.
Butterbur (common name: Butterbur or scientific name: Petasites japonicus) is a perennial shrub found in a part of Asia and North America as well as Europe. Extract extracted from the roots and leaves of butterbur has been used as a therapeutic substance for more than 2,000 years. At the present time, the extract of Petasites japonicus is commonly used to relax muscles, treated in the conditions such as abdominal pain in the stomach and intestines, convulsion of a smooth muscle, shows pain relief effect and may be used for headache (Eaton J., Townsend Lett, 2000, 202, 104-106). Also, it has been reported that Petasites japonicus has therapeutic effects on asthma and allergic diseases (Thomet OA, Simon HU, Int Arch Allergy Immunol, 2002, 129(2), 108-12). However, there has not yet been shown that Petasites japonicus has antioxidant effect. Thus, the present inventors have investigated plant resources having antioxidant activity to prepare a therapeutic and prophylactic agent of brain diseases and found that Petasites japonicus extract shows excellent antioxidant activity. Based on the above discovery, the present invention has been completed.